This investigation will test the hypothesis that metabolites of carbon tetrachloride or of phenobarbital interact with some macromolecular components of liver cells, probably chromatin and/or DNA, and thereby alter DNA synthesis. Acute administration of CCl4 produces a short period of DNA damage which reflects cell necrosis, but no evidence of DNA repair synthesis is seen. With continued and chronic administration of CCl4 DNA repair synthesis becomes prominent. These results indicate that CCl4 results in DNA damage in regenerating hepatocytes which is repaired by non-semiconservative DNA synthesis but CCl4 does not directly damage DNA in normal or quiescent hepatocytes. Additionally, during the course of chronic administration of CCl4, continuing alterations in DNA metabolism change the normal relationships between DNA synthesis in the nucleosomes and the internucleosome DNA strands. These changes in intrapolymeric synthetic rates induced by CCl4 are directly opposite to those which are seen in animals treated with the carcinogen, diethylnitrosamine. The significance of these changes to the emergence of liver tumors and comparative studies of phenobarbital and a combined regimen of phenobarbital and CCl4 represent the specific objectives which will be undertaken during the balance of this project period.